Abnormal Metabolism of Glycogen Phosphate as a Cause for Lafora Disease

Lafora disease is a progressive myoclonus epilepsy with onset in the teenage years followed by neurodegeneration and death within 10 years. A characteristic is the widespread formation of poorly branched, insoluble glycogen-like polymers (polyglucosan) known as Lafora bodies, which accumulate in neu...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:The Journal of biological chemistry 2008-12, Vol.283 (49), p.33816-33825
Hauptverfasser: Tagliabracci, Vincent S., Girard, Jean Marie, Segvich, Dyann, Meyer, Catalina, Turnbull, Julie, Zhao, Xiaochu, Minassian, Berge A., DePaoli-Roach, Anna A., Roach, Peter J.
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 33825
container_issue 49
container_start_page 33816
container_title The Journal of biological chemistry
container_volume 283
creator Tagliabracci, Vincent S.
Girard, Jean Marie
Segvich, Dyann
Meyer, Catalina
Turnbull, Julie
Zhao, Xiaochu
Minassian, Berge A.
DePaoli-Roach, Anna A.
Roach, Peter J.
description Lafora disease is a progressive myoclonus epilepsy with onset in the teenage years followed by neurodegeneration and death within 10 years. A characteristic is the widespread formation of poorly branched, insoluble glycogen-like polymers (polyglucosan) known as Lafora bodies, which accumulate in neurons, muscle, liver, and other tissues. Approximately half of the cases of Lafora disease result from mutations in the EPM2A gene, which encodes laforin, a member of the dual specificity protein phosphatase family that is able to release the small amount of covalent phosphate normally present in glycogen. In studies of Epm2a–/– mice that lack laforin, we observed a progressive change in the properties and structure of glycogen that paralleled the formation of Lafora bodies. At three months, glycogen metabolism remained essentially normal, even though the phosphorylation of glycogen has increased 4-fold and causes altered physical properties of the polysaccharide. By 9 months, the glycogen has overaccumulated by 3-fold, has become somewhat more phosphorylated, but, more notably, is now poorly branched, is insoluble in water, and has acquired an abnormal morphology visible by electron microscopy. These glycogen molecules have a tendency to aggregate and can be recovered in the pellet after low speed centrifugation of tissue extracts. The aggregation requires the phosphorylation of glycogen. The aggregrated glycogen sequesters glycogen synthase but not other glycogen metabolizing enzymes. We propose that laforin functions to suppress excessive glycogen phosphorylation and is an essential component of the metabolism of normally structured glycogen.
doi_str_mv 10.1074/jbc.M807428200
format Article
fullrecord <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2590708</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0021925820652346</els_id><sourcerecordid>69847019</sourcerecordid><originalsourceid>FETCH-LOGICAL-c601t-bca3056b5eeddd9d5057b27278f27e78d3fbe0f039ea43310cfee041338c8ccf3</originalsourceid><addsrcrecordid>eNp1kE1v1DAQhi1ERbcLV47gA-oty9jOh3NBqpayVNoKJKjEzXKc8cZVEm_tbKv-e1xlReGAD2NL8_j1-CHkLYMVgyr_eNuY1bVMJy45wAuyYCBFJgr26yVZAHCW1byQp-QsxltIK6_ZK3LKpCw4L9mCbC6a0YdB9_QaJ9343sWBeks3_aPxOxzp987HfacnpDpSTdf6EJFaH-hWp6rpZxdRR3xNTqzuI7457kty8-Xy5_prtv22uVpfbDNTApuyxmgBRdkUiG3b1m0BRdXwilfS8gor2QrbIFgQNepcCAbGIkLOhJBGGmPFknyac_eHZsDW4DgF3at9cIMOj8prp_7tjK5TO3-veFFDldwsyfkxIPi7A8ZJDS4a7Hs9oj9EVdYyr4DVCVzNoAk-xoD2zyMM1JN7ldyrZ_fpwru_R3vGj7IT8GEGOrfrHlxA1ThvOhwUl0LltUq_ZGXC3s-Y1V7pXXBR3fzgwASwosxL-RQkZwKT6XuHQUXjcDTYplAzqda7_w35Gzx7qGo</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>69847019</pqid></control><display><type>article</type><title>Abnormal Metabolism of Glycogen Phosphate as a Cause for Lafora Disease</title><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>PubMed Central</source><source>Alma/SFX Local Collection</source><creator>Tagliabracci, Vincent S. ; Girard, Jean Marie ; Segvich, Dyann ; Meyer, Catalina ; Turnbull, Julie ; Zhao, Xiaochu ; Minassian, Berge A. ; DePaoli-Roach, Anna A. ; Roach, Peter J.</creator><creatorcontrib>Tagliabracci, Vincent S. ; Girard, Jean Marie ; Segvich, Dyann ; Meyer, Catalina ; Turnbull, Julie ; Zhao, Xiaochu ; Minassian, Berge A. ; DePaoli-Roach, Anna A. ; Roach, Peter J.</creatorcontrib><description>Lafora disease is a progressive myoclonus epilepsy with onset in the teenage years followed by neurodegeneration and death within 10 years. A characteristic is the widespread formation of poorly branched, insoluble glycogen-like polymers (polyglucosan) known as Lafora bodies, which accumulate in neurons, muscle, liver, and other tissues. Approximately half of the cases of Lafora disease result from mutations in the EPM2A gene, which encodes laforin, a member of the dual specificity protein phosphatase family that is able to release the small amount of covalent phosphate normally present in glycogen. In studies of Epm2a–/– mice that lack laforin, we observed a progressive change in the properties and structure of glycogen that paralleled the formation of Lafora bodies. At three months, glycogen metabolism remained essentially normal, even though the phosphorylation of glycogen has increased 4-fold and causes altered physical properties of the polysaccharide. By 9 months, the glycogen has overaccumulated by 3-fold, has become somewhat more phosphorylated, but, more notably, is now poorly branched, is insoluble in water, and has acquired an abnormal morphology visible by electron microscopy. These glycogen molecules have a tendency to aggregate and can be recovered in the pellet after low speed centrifugation of tissue extracts. The aggregation requires the phosphorylation of glycogen. The aggregrated glycogen sequesters glycogen synthase but not other glycogen metabolizing enzymes. We propose that laforin functions to suppress excessive glycogen phosphorylation and is an essential component of the metabolism of normally structured glycogen.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M807428200</identifier><identifier>PMID: 18852261</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Disease Models, Animal ; Dual-Specificity Phosphatases - genetics ; Dual-Specificity Phosphatases - physiology ; Ethanol - chemistry ; Glycogen - chemistry ; Humans ; Lafora Disease - genetics ; Lafora Disease - metabolism ; Metabolism and Bioenergetics ; Mice ; Mice, Transgenic ; Models, Biological ; Models, Genetic ; Phosphates - chemistry ; Polymers - chemistry ; Protein Tyrosine Phosphatases, Non-Receptor - genetics ; Protein Tyrosine Phosphatases, Non-Receptor - metabolism ; Time Factors</subject><ispartof>The Journal of biological chemistry, 2008-12, Vol.283 (49), p.33816-33825</ispartof><rights>2008 © 2008 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.</rights><rights>Copyright © 2008, The American Society for Biochemistry and Molecular Biology, Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c601t-bca3056b5eeddd9d5057b27278f27e78d3fbe0f039ea43310cfee041338c8ccf3</citedby><cites>FETCH-LOGICAL-c601t-bca3056b5eeddd9d5057b27278f27e78d3fbe0f039ea43310cfee041338c8ccf3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2590708/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2590708/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18852261$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tagliabracci, Vincent S.</creatorcontrib><creatorcontrib>Girard, Jean Marie</creatorcontrib><creatorcontrib>Segvich, Dyann</creatorcontrib><creatorcontrib>Meyer, Catalina</creatorcontrib><creatorcontrib>Turnbull, Julie</creatorcontrib><creatorcontrib>Zhao, Xiaochu</creatorcontrib><creatorcontrib>Minassian, Berge A.</creatorcontrib><creatorcontrib>DePaoli-Roach, Anna A.</creatorcontrib><creatorcontrib>Roach, Peter J.</creatorcontrib><title>Abnormal Metabolism of Glycogen Phosphate as a Cause for Lafora Disease</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>Lafora disease is a progressive myoclonus epilepsy with onset in the teenage years followed by neurodegeneration and death within 10 years. A characteristic is the widespread formation of poorly branched, insoluble glycogen-like polymers (polyglucosan) known as Lafora bodies, which accumulate in neurons, muscle, liver, and other tissues. Approximately half of the cases of Lafora disease result from mutations in the EPM2A gene, which encodes laforin, a member of the dual specificity protein phosphatase family that is able to release the small amount of covalent phosphate normally present in glycogen. In studies of Epm2a–/– mice that lack laforin, we observed a progressive change in the properties and structure of glycogen that paralleled the formation of Lafora bodies. At three months, glycogen metabolism remained essentially normal, even though the phosphorylation of glycogen has increased 4-fold and causes altered physical properties of the polysaccharide. By 9 months, the glycogen has overaccumulated by 3-fold, has become somewhat more phosphorylated, but, more notably, is now poorly branched, is insoluble in water, and has acquired an abnormal morphology visible by electron microscopy. These glycogen molecules have a tendency to aggregate and can be recovered in the pellet after low speed centrifugation of tissue extracts. The aggregation requires the phosphorylation of glycogen. The aggregrated glycogen sequesters glycogen synthase but not other glycogen metabolizing enzymes. We propose that laforin functions to suppress excessive glycogen phosphorylation and is an essential component of the metabolism of normally structured glycogen.</description><subject>Animals</subject><subject>Disease Models, Animal</subject><subject>Dual-Specificity Phosphatases - genetics</subject><subject>Dual-Specificity Phosphatases - physiology</subject><subject>Ethanol - chemistry</subject><subject>Glycogen - chemistry</subject><subject>Humans</subject><subject>Lafora Disease - genetics</subject><subject>Lafora Disease - metabolism</subject><subject>Metabolism and Bioenergetics</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Models, Biological</subject><subject>Models, Genetic</subject><subject>Phosphates - chemistry</subject><subject>Polymers - chemistry</subject><subject>Protein Tyrosine Phosphatases, Non-Receptor - genetics</subject><subject>Protein Tyrosine Phosphatases, Non-Receptor - metabolism</subject><subject>Time Factors</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kE1v1DAQhi1ERbcLV47gA-oty9jOh3NBqpayVNoKJKjEzXKc8cZVEm_tbKv-e1xlReGAD2NL8_j1-CHkLYMVgyr_eNuY1bVMJy45wAuyYCBFJgr26yVZAHCW1byQp-QsxltIK6_ZK3LKpCw4L9mCbC6a0YdB9_QaJ9343sWBeks3_aPxOxzp987HfacnpDpSTdf6EJFaH-hWp6rpZxdRR3xNTqzuI7457kty8-Xy5_prtv22uVpfbDNTApuyxmgBRdkUiG3b1m0BRdXwilfS8gor2QrbIFgQNepcCAbGIkLOhJBGGmPFknyac_eHZsDW4DgF3at9cIMOj8prp_7tjK5TO3-veFFDldwsyfkxIPi7A8ZJDS4a7Hs9oj9EVdYyr4DVCVzNoAk-xoD2zyMM1JN7ldyrZ_fpwru_R3vGj7IT8GEGOrfrHlxA1ThvOhwUl0LltUq_ZGXC3s-Y1V7pXXBR3fzgwASwosxL-RQkZwKT6XuHQUXjcDTYplAzqda7_w35Gzx7qGo</recordid><startdate>20081205</startdate><enddate>20081205</enddate><creator>Tagliabracci, Vincent S.</creator><creator>Girard, Jean Marie</creator><creator>Segvich, Dyann</creator><creator>Meyer, Catalina</creator><creator>Turnbull, Julie</creator><creator>Zhao, Xiaochu</creator><creator>Minassian, Berge A.</creator><creator>DePaoli-Roach, Anna A.</creator><creator>Roach, Peter J.</creator><general>Elsevier Inc</general><general>American Society for Biochemistry and Molecular Biology</general><scope>6I.</scope><scope>AAFTH</scope><scope>FBQ</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20081205</creationdate><title>Abnormal Metabolism of Glycogen Phosphate as a Cause for Lafora Disease</title><author>Tagliabracci, Vincent S. ; Girard, Jean Marie ; Segvich, Dyann ; Meyer, Catalina ; Turnbull, Julie ; Zhao, Xiaochu ; Minassian, Berge A. ; DePaoli-Roach, Anna A. ; Roach, Peter J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c601t-bca3056b5eeddd9d5057b27278f27e78d3fbe0f039ea43310cfee041338c8ccf3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Animals</topic><topic>Disease Models, Animal</topic><topic>Dual-Specificity Phosphatases - genetics</topic><topic>Dual-Specificity Phosphatases - physiology</topic><topic>Ethanol - chemistry</topic><topic>Glycogen - chemistry</topic><topic>Humans</topic><topic>Lafora Disease - genetics</topic><topic>Lafora Disease - metabolism</topic><topic>Metabolism and Bioenergetics</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Models, Biological</topic><topic>Models, Genetic</topic><topic>Phosphates - chemistry</topic><topic>Polymers - chemistry</topic><topic>Protein Tyrosine Phosphatases, Non-Receptor - genetics</topic><topic>Protein Tyrosine Phosphatases, Non-Receptor - metabolism</topic><topic>Time Factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tagliabracci, Vincent S.</creatorcontrib><creatorcontrib>Girard, Jean Marie</creatorcontrib><creatorcontrib>Segvich, Dyann</creatorcontrib><creatorcontrib>Meyer, Catalina</creatorcontrib><creatorcontrib>Turnbull, Julie</creatorcontrib><creatorcontrib>Zhao, Xiaochu</creatorcontrib><creatorcontrib>Minassian, Berge A.</creatorcontrib><creatorcontrib>DePaoli-Roach, Anna A.</creatorcontrib><creatorcontrib>Roach, Peter J.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tagliabracci, Vincent S.</au><au>Girard, Jean Marie</au><au>Segvich, Dyann</au><au>Meyer, Catalina</au><au>Turnbull, Julie</au><au>Zhao, Xiaochu</au><au>Minassian, Berge A.</au><au>DePaoli-Roach, Anna A.</au><au>Roach, Peter J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Abnormal Metabolism of Glycogen Phosphate as a Cause for Lafora Disease</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2008-12-05</date><risdate>2008</risdate><volume>283</volume><issue>49</issue><spage>33816</spage><epage>33825</epage><pages>33816-33825</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>Lafora disease is a progressive myoclonus epilepsy with onset in the teenage years followed by neurodegeneration and death within 10 years. A characteristic is the widespread formation of poorly branched, insoluble glycogen-like polymers (polyglucosan) known as Lafora bodies, which accumulate in neurons, muscle, liver, and other tissues. Approximately half of the cases of Lafora disease result from mutations in the EPM2A gene, which encodes laforin, a member of the dual specificity protein phosphatase family that is able to release the small amount of covalent phosphate normally present in glycogen. In studies of Epm2a–/– mice that lack laforin, we observed a progressive change in the properties and structure of glycogen that paralleled the formation of Lafora bodies. At three months, glycogen metabolism remained essentially normal, even though the phosphorylation of glycogen has increased 4-fold and causes altered physical properties of the polysaccharide. By 9 months, the glycogen has overaccumulated by 3-fold, has become somewhat more phosphorylated, but, more notably, is now poorly branched, is insoluble in water, and has acquired an abnormal morphology visible by electron microscopy. These glycogen molecules have a tendency to aggregate and can be recovered in the pellet after low speed centrifugation of tissue extracts. The aggregation requires the phosphorylation of glycogen. The aggregrated glycogen sequesters glycogen synthase but not other glycogen metabolizing enzymes. We propose that laforin functions to suppress excessive glycogen phosphorylation and is an essential component of the metabolism of normally structured glycogen.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>18852261</pmid><doi>10.1074/jbc.M807428200</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 0021-9258
ispartof The Journal of biological chemistry, 2008-12, Vol.283 (49), p.33816-33825
issn 0021-9258
1083-351X
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2590708
source MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Alma/SFX Local Collection
subjects Animals
Disease Models, Animal
Dual-Specificity Phosphatases - genetics
Dual-Specificity Phosphatases - physiology
Ethanol - chemistry
Glycogen - chemistry
Humans
Lafora Disease - genetics
Lafora Disease - metabolism
Metabolism and Bioenergetics
Mice
Mice, Transgenic
Models, Biological
Models, Genetic
Phosphates - chemistry
Polymers - chemistry
Protein Tyrosine Phosphatases, Non-Receptor - genetics
Protein Tyrosine Phosphatases, Non-Receptor - metabolism
Time Factors
title Abnormal Metabolism of Glycogen Phosphate as a Cause for Lafora Disease
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-04T00%3A55%3A30IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Abnormal%20Metabolism%20of%20Glycogen%20Phosphate%20as%20a%20Cause%20for%20Lafora%20Disease&rft.jtitle=The%20Journal%20of%20biological%20chemistry&rft.au=Tagliabracci,%20Vincent%20S.&rft.date=2008-12-05&rft.volume=283&rft.issue=49&rft.spage=33816&rft.epage=33825&rft.pages=33816-33825&rft.issn=0021-9258&rft.eissn=1083-351X&rft_id=info:doi/10.1074/jbc.M807428200&rft_dat=%3Cproquest_pubme%3E69847019%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=69847019&rft_id=info:pmid/18852261&rft_els_id=S0021925820652346&rfr_iscdi=true